Hypercapnia is common in lung diseases such as chronic obstructive pulmonary disease, cystic fibrosis, and acute respiratory failure. "Permissive/therapeutic hypercapnia" has been proposed in the critical care setting for the treatment of acute respiratory distress syndrome (ARDS). However, the clinical course of many of these patients is often complicated by frequent and recurrent pulmonary infections contributing to increased morbidity and mortality. Given the limited research addressing the role of hypercapnia in lung infections, it is unclear whether hypercapnia is beneficial or can adversely affect pulmonary host defense. We have previously reported that hypercapnia impairs innate immunity by inhibition of several NF-?B-regulated pro-inflammatory cytokines critical for host defense and impairs phagocytosis. Furthermore, prolonged hypercapnia in the murine Pseudomonas aeruginosa pneumonia model suggests that hypercapnia leads to a decrease in bacterial clearance and increased mortality. Based on these observations, we hypothesize that hypercapnia impairs pulmonary host defense. We will explore three interrelated specific aims, to determine whether hypercapnia (1) impairs phagocytosis and (2) reactive oxygen species generation resulting in (3) increased bacterial dissemination associated with increased mortality in Pseudomonas aeruginosa pneumonia. Completion of the studies proposed in this project will provide novel information regarding the effects of hypercapnia on pulmonary host defense. The information obtained in this proposal may be used to evaluate new therapeutic strategies to alter the clinical course of patients with hypercapnia-related lung diseases. Dr. Gates has chosen a career in academic medicine and is striving to become an independent physician-scientist. She has been productive during her time in basic science research, but recognizes the importance of obtaining more skills and experience that will serve as a strong foundation for an independent investigator career. As an underrepresented minority, Dr. Gates hopes the K-01 award will provide her with the mentorship and experience that she requires for a successful academic career. She is in a rich environment at Northwestern University, in the Pulmonary and Critical Care Division that will provide research opportunities to promote her career development. She is in a department and division that are committed to her career development. With the mentorship of Dr. Jacob Sznajder and Dr. Peter Sporn, she is confident that she will acquire the necessary skills and critical thinking to become and independent, productive physician-scientist. Her short-term goals during this development process are to obtain more research skills and fundamental knowledge through hands-on experience as well as didactic lectures to establish a strong foundation for academic research in pulmonary disease. Long term, she desires to have a productive independent career as a physician-investigator, forming clinical questions from her patients and using basic science research to the explore the cellular and molecular mechanisms of pulmonary diseases, which could potentially lead to novel therapeutic options and/or change in current clinical practices in pulmonary medicine. PUBLIC HEALTH RELEVANCE: Patients with chronic lung diseases such as chronic obstructive pulmonary disease (COPD) often have elevated levels of carbon dioxide and frequently have recurrent infections. Research has shown that elevated levels of carbon dioxide may make these patients more susceptible to infections and make it more difficult for them to recover from infections. If this relationship is correct, there would be more options to improve prevention and treatment of infection in these patients.